Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids.
Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.
Beck
G
G
Hoechst AG, Frankfurt/M, West Germany.
Kesseler
K
K
Baader
E
E
Bartmann
W
W
Bergmann
A
A
Granzer
E
E
Jendralla
H
H
von Kerekjarto
B
B
Krause
R
R
Paulus
E
E
D000085:Acetates / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents; D055598:Chemical Phenomena; D002621:Chemistry; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D006538:Heptanoic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014961:X-Ray Diffraction
D000085:Acetates; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D011725:Pyridines; D011743:Pyrimidines; C062437:HR 780; D002784:Cholesterol